Type 1 diabetes (T1D) arises from the autoimmune destruction of the insulin-secreting beta cells of the pancreas resulting in complete dependence on exogenously administered insulin for survival. Twin studies indicate that susceptibility to T1D is, in part, genetically determined, but within families the disorder follows no clear mode of inheritance and is generally thought to result from the combined effects of multiple genes interacting with non-genetic factors. The extended pre-clinical period in T1D provides an excellent window to intervene in the autoimmune phase of pathogenesis with the goal of preventing the onset of frank disease. Identification of susceptibility genes provides opportunities for novel therapeutic interventions targeting their products and the biochemical pathways they impact, as well as for disease prediction that is crucial in defining populations in which therapies can be tested. Two genomic regions are generally agreed upon as containing susceptibility loci for T1D, the HLA region on 6p (IDDM1) and the insulin gene (INS) region on 1 1p (IDDM2). In order to identify additional loci that contribute to T1D pathogenesis, we have genome scanned a total of 412 T1D multiplex families of US origin, added data from 355 comparable UK T1D families, and carried out a joint analysis of the evidence for linkage to T1D. These studies provide significant evidence of linkage at 3 sites and suggestive evidence for 4 more. In this application we focus on the two regions that we judge the most promising from our linkage studies, 16q22-24, where the evidence of linkage is the most highly significant, and 10q25, where there is confirmation of linkage from independent studies. We have identified multiple markers with alleles in significant linkage disequilibrium with T1D in both of these regions. In the current application, we pursue these findings through comprehensive linkage disequilibrium mapping, characterization of all transcription units in the regions and functional studies of the relevant genes and their products. Our long-term goal is to define the genetic contributions to T1D pathogenesis and use this information to develop novel tools for prediction and prevention of T1D. [unreadable] [unreadable]